Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, The Key Laboratory of Digestive Diseases of Anhui Province, No. 218 Jixi Road, Hefei, Anhui, 230022, China.
Dig Dis Sci. 2013 Jan;58(1):107-14. doi: 10.1007/s10620-012-2304-3. Epub 2012 Jul 10.
Myosin light chain kinase (MLCK) plays a central role in the mechanisms of barrier dysfunction, and intestinal epithelial MLCK protein expression is upregulated in active ulcerative colitis (UC). ML-7, a MLCK inhibitor, has been used in many MLCK studies. However, the effect of ML-7 has never been estimated in colitis models. The aim of this study was to determine whether ML-7 can treat UC.
Experimental colitis was induced and ML-7 was administered by intraperitoneal injection. The disease activity index (DAI) scores were evaluated and colon tissue was collected for the assessment of histological changes, myeloperoxidase (MPO) activity, and tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-13 and interleukin (IL)-17 levels. The small intestinal mucosa was ultrastructurally examined, epithelial MLCK protein expression and enzymatic activity were determined, and intestinal permeability was assayed using FITC-dextran 4000 (FD-4) and Evans blue (EB).
ML-7 was found to be significantly effective in reducing the DAI scores and histological index scores, and decreasing MPO activity and TNF-α, IFN-γ, IL-13 and IL-17 levels. The small intestinal epithelial MLCK protein expression and enzymatic activity were downregulated by ML-7. The epithelial cells and intercellular tight junctions were ameliorated, and the amount of FD-4 in blood and EB permeating into the intestine were decreased by ML-7 in colitis mice.
ML-7 has a significant anti-colitis effect in colitis mice. It is mainly associated with the inhibition of the epithelial MLCK protein expression, resulting in ameliorated intestinal mucosal permeability.
肌球蛋白轻链激酶（MLCK）在屏障功能障碍的机制中起着核心作用，并且在活动性溃疡性结肠炎（UC）中，肠上皮细胞的 MLCK 蛋白表达上调。ML-7 是一种 MLCK 抑制剂，已在许多 MLCK 研究中使用。然而，ML-7 在结肠炎模型中的作用从未被评估过。本研究旨在确定 ML-7 是否可用于治疗 UC。
通过腹腔注射诱导实验性结肠炎，并给予 ML-7 治疗。评估疾病活动指数（DAI）评分，并收集结肠组织以评估组织学变化、髓过氧化物酶（MPO）活性以及肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ、白细胞介素（IL）-13 和白细胞介素（IL）-17 水平。观察小肠黏膜超微结构，测定上皮 MLCK 蛋白表达和酶活性，并使用 FITC-葡聚糖 4000（FD-4）和 Evans 蓝（EB）测定肠通透性。
ML-7 显著降低 DAI 评分和组织学指数评分，降低 MPO 活性和 TNF-α、IFN-γ、IL-13 和 IL-17 水平。ML-7 下调小肠上皮 MLCK 蛋白表达和酶活性。改善了上皮细胞和细胞间紧密连接，减少了结肠炎小鼠中 FD-4 在血液中的含量和 EB 渗透到肠道的量。
ML-7 在结肠炎小鼠中具有显著的抗结肠炎作用。它主要与抑制上皮 MLCK 蛋白表达有关，从而改善了肠道黏膜通透性。
